We have been at the forefront in establishing a new paradigm in cancer biology that imbues a critical function to key oncogenes, such as MYC, towards augmenting ribosome biogenesis and protein synthesis rates as an essential driver of tumorigenesis. Indeed, pioneering pharmacogenetic studies in my lab have established that MYC's oncogenic potential relies on protein synthesis control. Importantly, this suggests a novel avenue for the development of therapies to treat MYC-driven cancers by targeting the addiction of this undruggable oncogene to protein synthesis. However, despite the tremendous untapped potential for novel therapeutics, there is a large gap in our understanding of the cellular and molecular basis for synthetic lethal interactions between oncogenic MYC signaling and enhanced protein synthesis. We have exploited the addiction of MYC- overexpressing cells to elevated protein synthesis rates in order to reveal an entire network of synthetically lethal cellular processes and regulatory nodes that support and mediate MYC-dependent protein synthesis to promote tumorigenesis. Together, we have termed this addiction the MYC protein synthesis-dependent synthetic lethal network. Three critical nodes of this network include (1) an anabolic feed-forward circuit between protein synthesis and nucleotide production that sustains the biosynthetic and bioenergetic demands of MYC tumor cells (2) a novel cis-acting RNA regulatory signature in pro-tumorigenic mRNAs that confers MYC-dependent translational sensitivity, and (3) specialized translational reprogramming of the cancer cell genome. Collectively, these findings lay the foundation for this proposal, which seeks to open a new portal into our understanding of the molecular basis for the addiction of MYC-driven cancers to protein synthesis and identify novel therapeutic approaches that exploit this Achilles' heel of MYC-induced tumorigenesis. In Aim 1, we will define the mechanisms underlying the anabolic feed-forward circuitry that couples nucleotide metabolism to protein synthesis and assess its therapeutic implications in MYC-induced cancer. In Aim 2, we will determine the mechanism by which the PRTE, a specialized cis-regulatory element, couples protein and nucleotide biosynthesis in cancer. In Aim 3, we will define the contribution of global and specific modes of mRNA translation towards the genome-wide translational landscape of oncogenic MYC signaling, employing state-of-the-art ribosome profiling coupled to unique genetic mouse models. Together, these studies will provide unprecedented insight into translational remodeling of the cancer genome by MYC and will define an entire new layer of synthetic lethal interactions, providing the foundation for novel therapies targeting the currently undruggable MYC oncogene.